tbuckley/cabot-search huggingface dataset:
Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure
Authors: Venkata Garlapati, Michael Molitor, Thomas Michna, Gregory S. Harms, Stefanie Finger, Rebecca Jung, Jeremy Lagrange, Panagiotis Efentakis, Johannes Wild, Maike Knorr, Susanne Karbach, Sabine Wild, Ksenija Vujacic-Mirski, Thomas Münzel, Andreas Daiber, Moritz Brandt, Tommaso Gori, Hendrik Milting, Stefan Tenzer, Wolfram Ruf, Philip Wenzel
Journal: Journal of Clinical Investigation (2022)

Despite major advances in acute interventions for myocardial infarction (MI), adverse cardiac remodeling and excess fibrosis after MI causing ischemic heart failure (IHF) remain a leading cause of death worldwide. Here we identify a profibrotic coagulation signaling pathway that can be targeted for improved cardiac function following MI with persistent ischemia. Quantitative phosphoproteomics of cardiac tissue revealed an upregulated mitogen-activated protein kinase (MAPK) pathway in human IHF. Intervention in this pathway with trametinib improves myocardial function and prevents fibrotic remodeling in a murine model of non-reperfused MI. MAPK activation in MI requires myeloid cell signaling of protease-activated receptor 2 linked to the cytoplasmic domain of the coagulation initiator tissue factor (TF). They act upstream of pro-oxidant NOX2 NADPH oxidase, ERK1/2 phosphorylation, and activation of profibrotic TGF-β1. Specific targeting with the TF inhibitor nematode anticoagulant protein c2 (NAPc2) starting 1 day after established experimental MI averts IHF. Increased TF cytoplasmic domain phosphorylation in circulating monocytes from patients with subacute MI identifies a potential thromboinflammatory biomarker reflective of increased risk for IHF and suitable for patient selection to receive targeted TF inhibition therapy.
Intestinal neuropod cell GUCY2C regulates visceral pain
Authors: Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Journal: Journal of Clinical Investigation (2022)

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient — but not GUCY2C-deficient — neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling in VP that was comparable with chemically induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.
The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells
Authors: Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, Yi Sun
Journal: Journal of Clinical Investigation (2022)

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo. Here we report that UBE2C was indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C was required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibited tumor formation and extended the lifespan of mice. Mechanistically, KrasG12D induced expression of UBE2C, which coupled with APC/CCDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of mTORC signaling. Importantly, DEPTOR levels fluctuated during cell cycle progression in a manner dependent on UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene and tumor suppressor cascade that regulates cell cycle progression and autophagy and validates UBE2C an attractive target for lung cancer associated with Kras mutations.
Association of Baseline Adherence to Antihypertensive Medications With Adherence After Shelter-in-Place Guidance for COVID-19 Among US Adults
Authors: Brent M. Egan, Susan E. Sutherland, Cynthia I. Macri, Yi Deng, Ariungeral Gerelchuluun, Michael K. Rakotz, Stanley V. Campbell
Journal: JAMA Network Open (2022)

Adherence to selected antihypertensive medications (proportion of days covered [PDC]) declined after guidance to shelter in place for COVID-19.To determine whether PDC for all antihypertensive medications collectively fell from the 6 months before sheltering guidance (September 15, 2019, to March 14, 2020 [baseline]) compared with the first (March 15 to June 14, 2020) and second (June 15 to September 14, 2020) 3 months of sheltering and to assess the usefulness of baseline PDC for identifying individuals at risk for declining PDC during sheltering.This retrospective cohort study included a random sample of US adults obtained from EagleForce Health, a division of EagleForce Associates Inc. Approximately one-half of the adults were aged 40 to 64 years and one-half were aged 65 to 90 years, with prescription drug coverage, hypertension, and at least 1 antihypertensive medication prescription filled at a retail pharmacy during baseline.Prescription claims were used to assess (1) PDC at baseline and changes in PDC during the first and second 3 months of sheltering and (2) the association of good (PDC ≥ 80), fair (PDC 50-79), and poor (PDC < 50) baseline adherence with adherence during sheltering.A total of 27 318 adults met inclusion criteria (mean [SD] age, 65.0 [11.7] years; 50.7% women). Mean PDC declined from baseline (65.6 [95% CI, 65.2-65.9]) during the first (63.4 [95% CI, 63.0-63.8]) and second (58.9 [95% CI, 58.5-59.3]) 3 months after sheltering in all adults combined (P < .001 for both comparisons) and both age groups separately. Good, fair, and poor baseline adherence was observed in 40.0%, 27.8%, and 32.2% of adults, respectively. During the last 3 months of sheltering, PDC declined more from baseline in those with good compared with fair baseline adherence (-13.1 [95% CI, -13.6 to -12.6] vs -8.3 [95% CI, -13.6 to -12.6]; P < .001), whereas mean (SD) PDC increased in those with poor baseline adherence (mean PDC, 31.6 [95% CI, 31.3-31.9] vs 34.4 [95% CI, 33.8-35.0]; P < .001). However, poor adherence during sheltering occurred in 1034 adults (9.5%) with good baseline adherence, 2395 (31.6%) with fair baseline adherence, and 6409 (72.9%) with poor baseline adherence.These findings suggest that individuals with poor baseline adherence are candidates for adherence-promoting interventions irrespective of sheltering guidance. Interventions to prevent poor adherence during sheltering may be more useful for individuals with fair vs good baseline adherence.
Conservative Therapy for Acute and Subacute Back or Neck Pain
Authors: Erin E. Krebs, Elizabeth S. Goldsmith
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Technological Tools to Improve Communication in Patients With Hearing Loss
Authors: Tyler G. James, Michael M. McKee
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma
Authors: Matthew Ingham, Shing Lee, Brian A. Van Tine, Edwin Choy, Jay Oza, Sahil Doshi, Liner Ge, Peter Oppelt, Gregory Cote, Brian Corgiat, Naomi Sender, Sarah Sta Ana, Lavan Panchalingam, Emmanuel Petricoin, Gary K. Schwartz
Journal: Clinical Cancer Research (2022)

Abstract Purpose: To evaluate sitravatinib, an inhibitor of multiple receptor tyrosine kinases (RTK), for the treatment of well-differentiated/dedifferentiated liposarcoma (WD/DD LPS). Patients and Methods: This multicenter, open-label, Phase II trial enrolled patients with advanced WD/DD LPS who had received at least one prior systemic regimen and had progression within 12 weeks of enrollment. Patients received sitravatinib 150 mg (later amended to 120 mg) orally daily. A Simon two-stage design was used to evaluate for an improvement in the primary endpoint, progression-free rate at 12 weeks (PFR12), from 20% to 40%. Secondary endpoints included antitumor activity and safety. A subset of patients underwent paired biopsies analyzed using reverse-phase protein array. Results: Twenty-nine patients enrolled. Median age was 62 years and 31% had received 3 or more prior lines. Most patients (93%) had DDLPS or mixed WD/DD LPS. Overall, 12 of 29 patients (41%) were alive and progression-free at 12 weeks and the study met the primary endpoint. There were no confirmed responses. Median progression-free survival was 11.7 weeks [95% confidence interval (CI): 5.9–35.9] and median overall survival was 31.7 weeks (95% CI: 18.1–90.1). The most common treatment-related adverse events were diarrhea (59%), hypertension (52%), hoarseness (41%), mucositis (31%), and nausea (31%). Baseline expression of phospho-RTKs was not significantly different between patients with and without clinical benefit from sitravatinib, but the number of samples was small. Conclusions: Sitravatinib provided a PFR12 of 41% and meaningful disease control in a subset of patients with advanced, progressive WD/DD LPS.
Effects up to 20-Year Follow-Up of Preventive Cognitive Therapy in Adults Remitted from Recurrent Depression: The DELTA Study
Authors: Amanda M. Legemaat, Huibert Burger, Gert J. Geurtsen, Marlies Brouwer, Philip Spinhoven, Damiaan Denys, Claudi L. Bockting
Journal: Psychotherapy and Psychosomatics (2022)

Introduction: Major depressive disorder (MDD) is common, and recurrence rates are high. Preventive Cognitive Therapy (PCT), has been shown to prolong time to recurrence and reduce risk of recurrence(s) over 2–10 years in patients with recurrent depression. Objective: The aim of the study was to examine the effectiveness of PCT over 20 years on time to first recurrence, cumulative proportion of first recurrences, percentage of depression-free time, mean severity of recurrences, and the number of recurrences within a patient. Methods: Adults remitted from recurrent MDD were randomized to PCT or Treatment As Usual (TAU). Clinical outcomes were assessed using the SCID over 20 years. We used Cox regression analyses, Kaplan-Meier analyses, ANOVA, and negative binomial regression and tested for interaction with the number of previous episodes. Results: There was a significant interaction effect for number of previous episodes with treatment condition on time to first recurrence (Wald[1, n = 172] = 8.840, p = 0.003). For participants with more than 3 previous episodes, the mean time to recurrence was 4.8 years for PCT versus 1.6 years for TAU; the cumulative proportion of first recurrences was 87.5% for PCT and 100% for TAU. For participants with more than 3 previous episodes, exploratory analyses suggest that PCT had 53% less recurrences and percentage of depression-free time was significantly higher compared to TAU. There were no significant effects on mean severity. Conclusions: Up to 20 years, for MDD patients with more than 3 previous episodes, those who received PCT had significantly longer time to a first recurrence and lower recurrence risk and may have less recurrences and more depression-free time compared to TAU. This suggests long term protective effects of PCT up to 20-years.
A Dynamic Membrane‐Active Glycopeptide for Enhanced Protection of Human Red Blood Cells against Freeze‐Stress
Authors: Shuhui Gao, Qingjing Niu, Yan Wang, Lixia Ren, Jinghui Chong, Kongying Zhu, Xiaoyan Yuan
Journal: Advanced Healthcare Materials (2022)

Abstract Intracellular delivery of freezing‐tolerant trehalose is crucial for cryopreservation of red blood cells (RBCs) and previous strategies based on membrane‐disruptive activity usually generate severe hemolysis. Herein, a dynamic membrane‐active glycopeptide is developed by grafting with 25% maltotriose and 50% p ‐benzyl alcohol for the first time to effectively facilitate entry of membrane‐impermeable trehalose in human RBCs with low hemolysis. Results of the mechanism acting on cell membranes suggest that reversible adsorption of such benzyl alcohol‐grafted glycopeptide on cell surfaces upon weak perturbation with phospholipids and dynamic transition toward membrane stabilization are essential for keeping cellular biofunctions. Furthermore, the functionalized glycopeptide is indicative of typical α ‐helical/ β ‐sheet structure‐driven regulations of ice crystals during freeze−thaw, thereby strongly promoting efficient cryopreservation. Such all‐in‐one glycopeptide enables achieving both high cell recovery post‐thaw &gt;85% and exceptional cryosurvival &gt;95% in direct freezing protocols. The rationally designed benzyl alcohol‐modified glycopeptide permits the development of a competent platform with high generality for protection of blood cells against freeze‐stress.
Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia
Authors: Kendra L. Sweet, Jorge E. Cortes, Jane F. Apperley, Mel Mann, Michael J. Mauro, Vivian G. Oehler, Cristina Ruiz, Charles A. Schiffer, Lori A. Ehrlich, Gulsum E. Pamuk, Joseph Wynne, Gautam U. Mehta, R. Angelo de Claro, Marc R. Theoret, B. Douglas Smith, Kelly J. Norsworthy
Journal: Clinical Cancer Research (2022)

Abstract The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.
An interpretable artificial intelligence system for detecting risk factors of gastroesophageal variceal bleeding
Authors: Jing Wang, Zhengqiang Wang, Mingkai Chen, Yong Xiao, Shi Chen, Lianlian Wu, Liwen Yao, Xiaoda Jiang, Jiao Li, Ming Xu, Mengjuan Lin, Yijie Zhu, Renquan Luo, Chenxia Zhang, Xun Li, Honggang Yu
Journal: npj Digital Medicine (2022)

Bleeding risk factors for gastroesophageal varices (GEV) detected by endoscopy in cirrhotic patients determine the prophylactical treatment patients will undergo in the following 2 years. We propose a methodology for measuring the risk factors. We create an artificial intelligence system (ENDOANGEL-GEV) containing six models to segment GEV and to classify the grades (grades 1-3) and red color signs (RC, RC0-RC3) of varices. It also summarizes changes in the above results with region in real time. ENDOANGEL-GEV is trained using 6034 images from 1156 cirrhotic patients across three hospitals (dataset 1) and validated on multicenter datasets with 11009 images from 141 videos (dataset 2) and in a prospective study recruiting 161 cirrhotic patients from Renmin Hospital of Wuhan University (dataset 3). In dataset 1, ENDOANGEL-GEV achieves intersection over union values of 0.8087 for segmenting esophageal varices and 0.8141 for gastric varices. In dataset 2, the system maintains fairly accuracy across images from three hospitals. In dataset 3, ENDOANGEL-GEV surpasses attended endoscopists in detecting RC of GEV and classifying grades (p < 0.001). When ranking the risk of patients combined with the Child‒Pugh score, ENDOANGEL-GEV outperforms endoscopists for esophageal varices (p < 0.001) and shows comparable performance for gastric varices (p = 0.152). Compared with endoscopists, ENDOANGEL-GEV may help 12.31% (16/130) more patients receive the right intervention. We establish an interpretable system for the endoscopic diagnosis and risk stratification of GEV. It will assist in detecting the first bleeding risk factors accurately and expanding the scope of quantitative measurement of diseases.
Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells
Authors: Katherine A. Kaiser, Lucas F. Loffredo, Kenia de los Santos-Alexis, Olivia R. Ringham, Nicholas Arpaia
Journal: The Journal of Experimental Medicine (2022)

Following respiratory viral infection, regeneration of the epithelial barrier is required to preserve lung function and prevent secondary infections. Lung regulatory T (Treg) cells are critical for maintaining blood oxygenation following influenza virus infection through production of the EGFR ligand amphiregulin (Areg); however, how Treg cells engage with progenitors within the alveolar niche is unknown. Here, we describe local interactions between Treg cells and an Areg-responsive population of Col14a1+EGFR+ lung mesenchymal cells that mediate type II alveolar epithelial (AT2) cell-mediated regeneration following influenza virus infection. We propose a mechanism whereby Treg cells are deployed to sites of damage and provide pro-survival cues that support mesenchymal programming of the alveolar niche. In the absence of fibroblast EGFR signaling, we observe impaired AT2 proliferation and disrupted lung remodeling following viral clearance, uncovering a crucial immune/mesenchymal/epithelial network that guides alveolar regeneration.
Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases
Authors: Xiaohuan Xia, Yi Wang, Jialin C. Zheng
Journal: Translational Neurodegeneration (2022)

Abstract Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.